Jin Zhou
Email Address
gmszj@nus.edu.sg
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Publication Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease(OAE Publishing Inc., 2021-01-01) Zhou, J; Tripathi, M; Sinha, RA; Singh, BK; Yen, PM; Dr Brijesh Kumar Singh; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOLNon-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder worldwide. It comprises a spectrum of conditions that range from steatosis to non-alcoholic steatohepatitis, with progression to cirrhosis and hepatocellular carcinoma. Currently, there is no FDA-approved pharmacological treatment for NAFLD. The pathogenesis of NAFLD involves genetic and environmental/host factors, including those that cause changes in intestinal microbiota and their metabolites. In this review, we discuss recent findings on the relationship(s) of microbiota signature with severity of NAFLD and the role(s) microbial metabolites in NAFLD progression. We discuss how metabolites may affect NAFLD progression and their potential to serve as biomarkers for NAFLD diagnosis or therapeutic targets for disease management.Publication Short chain fatty acids induce UCP2-mediated autophagy in hepatic cells (vol 480, pg 461, 2016)(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2017-01-22) Iannucci, Liliana F; Sun, Jingfeng; Singh, Brijesh K; Zhou, Jin; Kaddai, Vincent A; Lanni, Antonia; Yen, Paul M; Sinha, Rohit A; Dr Brijesh Kumar Singh; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOLThe authors regret for typographical errors in the Figure legends 1 and 2 where MAP1MAP1LC3 has been now replaced by MAP1LC3. Also there was a missing text added in the Figure legend 3E. Corrections were done in the Material and methods section at page 462 where T3 was replaced with SCFAs and 13 weeks with 12 weeks.Publication Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression(Elsevier BV, 2021-11-01) Bruinstroop, E; Zhou, J; Tripathi, M; Yau, WW; Boelen, A; Singh, BK; Yen, PM; Dr Brijesh Kumar Singh; DUKE-NUS MEDICAL SCHOOLObjective: Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive nonalcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of prohormone thyroxine (T4) have a higher incidence of NAFLD, and thyroid hormone treatment is very promising in all patients with NAFLD. Deiodinase type 1 (Dio1) is a hepatic enzyme that converts T4 to the bioactive T3 and therefore regulates thyroid hormone availability within hepatocytes. We investigated the role of this intrahepatic regulation during the progression of NAFLD. Methods: We investigated hepatic thyroid hormone metabolism in two NAFLD models: wild-type mice fed a Western diet with fructose and Leprdb mice fed a methionine- and choline-deficient diet. AAV8-mediated liver-specific Dio1 knockdown was employed to investigate the role of Dio1 during the progression of NAFLD. Intrahepatic thyroid hormone levels, deiodinase activity, and metabolic parameters were measured. Results: Dio1 expression and activity were increased in the early stages of NAFLD and were associated with an increased T3/T4 ratio. Prevention of this increase by AAV8-mediated liver-specific Dio1 knockdown increased hepatic triglycerides and cholesterol and decreased the pACC/ACC ratio and acylcarnitine levels, suggesting there was lower β-oxidation. Dio1 siRNA KD in hepatic cells treated with fatty acids showed increased lipid accumulation and decreased oxidative phosphorylation. Conclusion: Hepatic Dio1 gene expression was modulated by dietary conditions, was increased during hepatosteatosis and early NASH, and regulated hepatic triglyceride content. These early adaptations likely represent compensatory mechanisms that reduce hepatosteatosis and prevent NASH progression.Publication Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue(CELL PRESS, 2021-05-21) Yau, Winifred W; Wong, Kiraely Adam; Zhou, Jin; Thimmukonda, Nivetha Kanakaram; Wu, Yajun; Bay, Boon-Huat; Singh, Brijesh Kumar; Yen, Paul Michael; Dr Brijesh Kumar Singh; ANATOMY; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOLAutophagy plays an important role in lipid breakdown, mitochondrial turnover, and mitochondrial function during brown adipose tissue (BAT) activation by thyroid hormone, but its role in BAT during adaptive thermogenesis remains controversial. Here, we examined BAT from mice exposed to 72 h of cold challenge as well as primary brown adipocytes treated with norepinephrine and found increased autophagy as well as increased β-oxidation, mitophagy, mitochondrial turnover, and mitochondrial activity. To further understand the role of autophagy of BAT in vivo, we generated BAT-specific Atg5 knockout (Atg5cKO) mice and exposed them to cold for 72 h. Interestingly, BAT-specific Atg5cKO mice were unable to maintain body temperature after chronic cold exposure and displayed deranged mitochondrial morphology and reactive oxygen species damage in their BAT. Our findings demonstrate the critical role of autophagy in adaptive thermogenesis, fatty acid metabolism, and mitochondrial function in BAT during chronic cold exposure.Publication Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells(Frontiers Media SA, 2020-09-30) Rajak, S; Iannucci, LF; Zhou, J; Anjum, B; George, N; Singh, BK; Ghosh, S; Yen, PM; Sinha, RA; Dr Brijesh Kumar Singh; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOLThe hepatic mevalonate (MVA) pathway, responsible for cholesterol biosynthesis, is a therapeutically important metabolic pathway in clinical medicine. Using an unbiased transcriptomics approach, we uncover a novel role of Unc-51 like autophagy activating kinase 1 (ULK1) in regulating the expression of the hepatic de novo cholesterol biosynthesis/MVA pathway genes. Genetic silencing of ULK1 in non-starved mouse (AML-12) and human (HepG2) hepatic cells as well as in mouse liver followed by transcriptome and pathway analysis revealed that the loss of ULK1 expression led to significant down-regulation of genes involved in the MVA/cholesterol biosynthesis pathway. At a mechanistic level, loss of ULK1 led to decreased expression of SREBF2/SREBP2 (sterol regulatory element binding factor 2) via its effects on AKT-FOXO3a signaling and repression of SREBF2 target genes in the MVA pathway. Our findings, therefore, discover ULK1 as a novel regulator of cholesterol biosynthesis and a possible druggable target for controlling cholesterol-associated pathologies.Publication Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH(NATURE RESEARCH, 2021-01-04) Dong, Jinrui; Viswanathan, Sivakumar; Adami, Eleonora; Singh, Brijesh K; Chothani, Sonia P; Ng, Benjamin; Lim, Wei Wen; Zhou, Jin; Tripathi, Madhulika; Ko, Nicole SJ; Shekeran, Shamini G; Tan, Jessie; Lim, Sze Yun; Wang, Mao; Lio, Pei Min; Yen, Paul M; Schafer, Sebastian; Cook, Stuart A; Widjaja, Anissa A; Dr Brijesh Kumar Singh; DEAN'S OFFICE (MEDICINE); DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOLIL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.Publication Decreased autophagy and fuel switching occur in a senescent hepatic cell model system(IMPACT JOURNALS LLC, 2020-07-31) Singh, Brijesh Kumar; Tripathi, Madhulika; Sandireddy, Reddemma; Tikno, Keziah; Zhou, Jin; Yen, Paul Michael; Dr Brijesh Kumar Singh; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOLAlthough aging in the liver contributes to the development of chronic liver diseases such as NAFLD and insulin resistance, little is known about the molecular and metabolic details of aging in hepatic cells. To examine these issues, we used sequential oxidative stress with hydrogen peroxide to induce premature senescence in AML12 hepatic cells. The senescent cells exhibited molecular and metabolic signatures, increased SA-βGal and γH2A. X staining, and elevated senescence and pro-inflammatory gene expression that resembled livers from aged mice. Metabolic phenotyping showed fuel switching towards glycolysis and mitochondrial glutamine oxidation as well as impaired energy production. The senescent AML12 cells also had increased mTOR signaling and decreased autophagy which likely contributed to the fuel switching from β-oxidation that occurred in normal AML12 cells. Additionally, senescence-associated secretory phenotype (SASP) proteins from conditioned media of senescent cells sensitized normal AML12 cells to palmitate-induced toxicity, a known pathological effect of hepatic aging. In summary, we have generated senescent AML12 cells which displayed the molecular hallmarks of aging and also exhibited the aberrant metabolic phenotype, mitochondrial function, and cell signaling that occur in the aged liver.Publication Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging(IMPACT JOURNALS LLC, 2017-02-01) Zhou, Jin; Chong, Shu Yun; Lim, Andrea; Singh, Brijesh K; Sinha, Rohit A; Salmon, Adam B; Yen, Paul M; Dr Brijesh Kumar Singh; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); CANCER SCIENCE INSTITUTE OF SINGAPORE; DUKE-NUS MEDICAL SCHOOLAging causes a general decline in cellular metabolic activity, and function in different tissues and whole body homeostasis. However, the understanding about the metabolomic and autophagy changes in skeletal muscle and heart during aging is still limited. We thus examined markers for macroautophagy, chaperone-mediated autophagy (CMA), mitochondrial quality control, as well as cellular metabolites in skeletal and cardiac muscle from young (5 months old) and aged (27 months old) mice. We found decreased autophagic degradation of p62 and increased ubiquitinated proteins in both tissues from aged mice, suggesting a decline in macroautophagy during aging. In skeletal muscle from aged mice, there also was a decline in LC3B-I conjugation to phosphatidylethanolamine (PE) possibly due to decreased protein levels of ATG3 and ATG12-ATG5. The CMA markers, LAMP-2A and Hsc70, and mitochondrial turnover markers, Drp1, PINK1 and PGC1a also were decreased. Metabolomics analysis showed impaired β-oxidation in heart of aged mice, whereas increased branched-chain amino acids (BCAAs) and ceramide levels were found in skeletal muscle of aged mice that in turn, may contribute to insulin resistance in muscle. Taken together, our studies showed similar declines in macroautophagy but distinct effects on CMA, mitochondrial turnover, and metabolic dysfunction in muscle vs. heart during aging.Publication Loss of ULK1 increases RPS6KB1-NCOR1 repression of NR1H/LXR-mediated Scd1 transcription and augments lipotoxicity in hepatic cells(TAYLOR & FRANCIS INC, 2017-01-01) Sinha, Rohit Anthony; Singh, Brijesh K; Zhou, Jin; Xie, Sherwin; Farah, Benjamin L; Lesmana, Ronny; Ohba, Kenji; Tripathi, Madhulika; Ghosh, Sujoy; Hollenberg, Anthony N; Yen, Paul M; Dr Brijesh Kumar Singh; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOLLipotoxicity caused by saturated fatty acids (SFAs) induces tissue damage and inflammation in metabolic disorders. SCD1 (stearoyl-coenzyme A desaturase 1) converts SFAs to mono-unsaturated fatty acids (MUFAs) that are incorporated into triglycerides and stored in lipid droplets. SCD1 thus helps protect hepatocytes from lipotoxicity and its reduced expression is associated with increased lipotoxic injury in cultured hepatic cells and mouse models. To further understand the role of SCD1 in lipotoxicity, we examined the regulation of Scd1 in hepatic cells treated with palmitate, and found that NR1H/LXR (nuclear receptor subfamily 1 group H) ligand, GW3965, induced Scd1 expression and lipid droplet formation to improve cell survival. Surprisingly, ULK1/ATG1 (unc-51 like kinase) played a critical role in protecting hepatic cells from SFA-induced lipotoxicity via a novel mechanism that did not involve macroautophagy/autophagy. Specific loss of Ulk1 blocked the induction of Scd1 gene transcription by GW3965, decreased lipid droplet formation, and increased apoptosis in hepatic cells exposed to palmitate. Knockdown of ULK1 increased RPS6KB1 (ribosomal protein S6 kinase, polypeptide 1) signaling that, in turn, induced NCOR1 (nuclear receptor co-repressor 1) nuclear uptake, interaction with NR1H/LXR, and recruitment to the Scd1 promoter. These events abrogated the stimulation of Scd1 gene expression by GW3965, and increased lipotoxicity in hepatic cells. In summary, we have identified a novel autophagy-independent role of ULK1 that regulates NR1H/LXR signaling, Scd1 expression, and intracellular lipid homeostasis in hepatic cells exposed to a lipotoxic environment.Publication PD-linked CHCHD2 mutations impair CHCHD10 and a MICOS complex leading to mitochondria dysfunction(OXFORD UNIV PRESS, 2019-04-01) Zhou, Wei; Ma, Dongrui; Sun, Alfred Xuyang; Tran, Hoang-Dai; Ma, Dong-Liang; Singh, Brijesh K; Zhou, Jin; Zhang, Jinyan; Wang, Danlei; Zhao, Yi; Yen, Paul M; Goh, Eyleen; Tan, Eng-King; Dr Brijesh Kumar Singh; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOLCoiled-coil-helix-coiled-coil-helix domain containing protein 2 (CHCHD2) mutations were linked with autosomal dominant Parkinson's disease (PD) and recently, Alzheimer's disease/frontotemporal dementia. In the current study, we generated isogenic human embryonic stem cell (hESC) lines harboring PD-associated CHCHD2 mutation R145Q or Q126X via clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) method, aiming to unravel pathophysiologic mechanism and seek potential intervention strategy against CHCHD2 mutant-caused defects. By engaging super-resolution microscopy, we identified a physical proximity and similar distribution pattern of CHCHD2 along mitochondria with mitochondrial contact site and cristae organizing system (MICOS), a large protein complex maintaining mitochondria cristae. Isogenic hESCs and differentiated neural progenitor cells (NPCs) harboring CHCHD2 R145Q or Q126X mutation showed impaired mitochondria function, reduced CHCHD2 and MICOS components and exhibited nearly hollow mitochondria with reduced cristae. Furthermore, PD-linked CHCHD2 mutations lost their interaction with coiled-coil-helix-coiled-coil-helix domain containing protein 10 (CHCHD10), while transient knockdown of either CHCHD2 or CHCHD10 reduced MICOS and mitochondria cristae. Importantly, a specific mitochondria-targeted peptide, Elamipretide/MTP-131, now tested in phase 3 clinical trials for mitochondrial diseases, was found to enhance CHCHD2 with MICOS and mitochondria oxidative phosphorylation enzymes in isogenic NPCs harboring heterozygous R145Q, suggesting that Elamipretide is able to attenuate CHCHD2 R145Q-induced mitochondria dysfunction. Taken together, our results suggested CHCHD2-CHCHD10 complex may be a novel therapeutic target for PD and related neurodegenerative disorders, and Elamipretide may benefit CHCHD2 mutation-linked PD.